Abstract
Background and Objective
Guanfacine extended-release (guanfacine XR) could be a useful treatment option for children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). As an initial step in the development in Japan, the pharmacokinetics, safety and tolerability were assessed in healthy Japanese and non-Hispanic Caucasian adults.
Methods
A Phase 1, double-blind, randomized, placebo-controlled, single- and multiple-oral dose escalation study of guanfacine XR was conducted. Healthy Japanese and Caucasian subjects received guanfacine XR 1 mg orally in the morning on Day 1. Following safety assessments, subjects subsequently received guanfacine XR 1 mg (Days 4–8), 2 mg (Days 9–13), 3 mg (Days 14–18), and 4 mg (Days 19–23) once daily, followed by a taper-down period. Single- and multiple-dose pharmacokinetic parameters were estimated based on plasma concentration–time data and urine concentration data of guanfacine by non-compartmental analysis.
Results
A total of 30 male subjects (15 Japanese and 15 Caucasian, active:placebo = 12:3) were enrolled. Of those receiving guanfacine XR, 11/12 (91.7%) subjects in each active drug group completed the study. Following multiple doses, the mean area under the plasma concentration–time curves of guanfacine were 9–22% greater for Caucasian subjects than Japanese subjects in the 1–3 mg dose range and 54% greater for the 4 mg. Guanfacine XR was generally well tolerated by both ethnic groups, with most adverse events being mild in both groups. There were no serious or severe adverse events during the study and no adverse events led to withdrawal from the study.
Conclusions
Exposure to guanfacine in Japanese subjects tended to be lower than in Caucasian subjects. Guanfacine XR was generally well tolerated and safety profiles were similar for Japanese and Caucasian subjects.
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Acknowledgments
The authors would like to thank Dr. Kennichi Furihata at P-One clinic, Medical corporation of Keiko Kaikai (Tokyo, Japan) for conducting the study.
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Funding
This study was funded by Shionogi & Co., Ltd. and Shire Development, LLC. Editorial assistance in formatting, proofreading and copy editing, as well as coordination and collation of comments was provided by Caudex, Oxford, UK, funded by Shire International GmbH.
Conflicts of Interest
Yumiko Matsuo, Masafumi Okita, and Toshihiro Wajima are employees of Shionogi & Co., Ltd. James Ermer was an employee of Shire at the time that the study was conducted and is now an independent consultant.
Ethical Approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Prior to the initiation of the study, the institutional review board (IRB) of P-One Clinic, Keikokai Medical Corporation reviewed the appropriateness of implementation of the study based on the documents submitted to the IRB by the sponsor, including the study protocol, sample case report form (CRF), and sample informed consent form/written information for subjects.
Informed Consent
Informed consent was obtained from all individual participants included in the study.
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Matsuo, Y., Okita, M., Ermer, J. et al. Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Guanfacine Extended-Release Formulation in Healthy Japanese and Caucasian Male Adults. Clin Drug Investig 37, 745–753 (2017). https://doi.org/10.1007/s40261-017-0527-y
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DOI: https://doi.org/10.1007/s40261-017-0527-y